6beta, 19-oxido-16, 17-acetals and ketals of the pregnane series



United States Patent 3,326,904 6p,19-0XlD0-16,l7-ACETALS AND KETALS OF THE PREGNANE SERIES Patrick A. Diassi, Westfield, N.J., assignor to E. R. Squibb & Sons Inc, New York, N.Y., a corporation of Delaware No Drawing. Filed Oct. 15, 1965, Ser. No. 496,679 10 Claims. (Cl. 260-23955) and the 4,5 or 1,2,4,5 unsaturates thereof, i.e., wherein the linkage x is either a single bond or double bond and the linkage y is either a single bond or double bond.

P is hydrogen, lower alkyl, halo lower alkyl, carboxy lower alkyl (or a salt or ester thereof), monocyclic cycloalkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic or monocyclic heterocyclic lower alkyl; Q is lower alkyl, halo lower alkyl, carboxy lower alkyl (or a salt or ester thereof), monocyclic cycloalkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic or monocyclic heterocyclic lower alkyl or together with the carbon atom to which they are joined P and Q are cycloalkyl or monocyclic heterocyclic.

The compounds of this invention may be prepared as illustrated by the following flow diagrams wherein P and Q are as hereinbefore defined and R and R represent hydrogen or acyl.

Br$R Br 3,326,904 Patented June 20, 1967 The compounds of this invention are prepared by first interacting A -pregnane 3fl,16oc,l7oc triol-20-one (Compounds A) with an aldehyde or ke-tone of the formula wherein P and Q are as above defined, and recovering the resultant acetal or ketal derivative. The reaction is preferably carried out by treating a suspension or solution of the steroid in the aldehyde or ketone (or an organic solvent if the aldehyde or ketone is a solid) with an acid catalyst (e.g., perchloric acid, p-toluenesulfonic acid, hydrochloric acid, etc.) and neutralizing the acid.

Suitable aldehyde and ketone reactants include lower alkanals of at least two carbon atoms, such as paraldehyde, propan al, and hexanal; di(lower alkyl)ketones, such as acetone, diethylketone, dibutylketone, methylet-hylketone, and methylisobutylketone; cycloalkanones, such as cyclobutanone, cyclopentanone, cyclohexanone, suberone, and cyclohexanone; mono and dicycloalkyl ketones, such as cyclohexylmethylketone and dicyclopropylketone, halo-lower alkan als, such as chloral hydrate, trifluoroacetaldehyde hemiacetal, and heptafluorobutanal ethyl hemiacetal; halo-lower alkanones, such as 1,1,1-t-rifluoroacetone; monocyclic carbocyclic aromatic aldehydes, such as benzaldehyde, halobenzaldehydes -(e.g., p-chlorobenzaldehyde and p-fluorobenzaldehyde), lower allcoxybenzaldehydes (e.g., o-anisaldehyde), di(lower alkoxy)benzaldehydes (e.g., veratraldehyde), hydroxybenzaldehydes (e.g., salicylaldehyde), dihydroxybenzaldehydes (e.g., resorcylaldehyde), lower alkyl benzaldehydes (e.g., m-tolualdehyde and p-ethylbenzaldehyde), di(lower alkyl)benzaldehydes (e.g., o,p dimethylbenzaldehyde), nitrobenzaldehydes, acylamidobenzaldehydes (e.g., N acetylanthranilaldehyde), and cyanobenzaldehydes; monocyclic carbocyclic aromatic lower alkanals, such as phenylacetaldehyde, a-phenylpropionaldehyde, fi-phenylpropionaldehyde, A-phenylbutyraldehyde, and aromatically substituted halo, lower alkoxy, hydroxy, lower alkyl, nitro, acylamido and cyano derivatives thereof; monocyclic heterocyclic aldehydes, such as picolinaldehydes, furfural, thiophene carbonals, and halo, lower alkoxy, hydroxy, lower alkyl, nitro, and cyano derivatives thereof; monocyclic heterocyclic lower alkanals; l-(monocylic carbocyclic aromatic) substituted lower alkanals, such as acetophenone, (1,0:,u-trifiuoroacetophenone, propiophenone, butyrophenone, valerophenone, isocaprophenone, halo-phenyl lower alkyl ketones (e.g., p-chloroacetophenone and p-chloropropiophenone), (lower alkoxy) phenyl lower alkyl ketones (e.g., p-anisyl methyl ketone) di(lower alkoxy)phenyl lower alkyl ketones, hydroxyphenyl lower alkyl ketones, dihy-droxyphenyl lower alkyl ketones (e.g., resacetophenone), (lower alkyl)phenyl lower alkyl ketones (e.g., methyl p-tolyl ketone), di(lower alky1)phenyl lower alkyl ketones (o,p-xylyl methyl ketone), nitrophenyl lower alkyl ketones (e.g., p-nitroacetophenone), acylamidophenyl lower alkyl ketones (e.g., acetyl anilines), and cyanophenyl lower alkyl ketones; benzophenone, and mono or bis substituted halo, lower alkoxy, hydroxy, lower alkyl, nitro, acylamido and cyano derivatives thereof; monocyclic carbocyclic aromatic lower alkanones, such as l-phenyl-3-butanone and l-phenyl-4- pentanone, and aromatically substituted derivatives thereof; l-(monocyclic heterocyclic) substituted lower alkanals, such as Z-acetylfuran, Z-benzoylfuran, and 2-acetylthiophenone; oxo substituted monocyclic heterocyclics, such as alloxan; monocyclic heterocyclic lower alkanones; and x0 lower alkanoic acids such as glyoxylic pyruvic, acetoacetic, fl-ketopropionic, a-ketobutyric, levulinic, ketooaproic and fi-ketocaprylic acid [as well as salts and esters thereof, such as the lower alkyl esters (e.g., methyl and ethyl) The resultant product may then be converted to its 3- ester derivative in the usual manner by reacting with the desired acylating agent (e.g., acyl chloride or acid anhydride) in the process of a base, such as pyridine to yield Compounds B. Although any ester can be prepared, the preferred esters are those wit-h hydrocarbon carboxylic acids of less than 12 carbon atoms as exemplified by the lower alkanoic acids (e.g., acetic, propionic, butyric, tertpentanoic acid), lower alkenoic acids, the monocyclic a-ryl carbocyclic acids (e.g., benzoic and toluic acids), aryl lower alkanoic acids (e.g., phena-cetic and B-phenylpropionic acid), the cycloalkane carboxylic acids and the cycloalkene carboxylic acids.

The 3-este-r compounds thus obtained, are then treated with N-bromoacetamide, in an acid medium, to yield the 3-esters of the 16a,17x-ketal or acetal derivatives of 5abromopregnane-3B,6B,l6a,17a-tetrol-20-one (Compounds C).

The 3-ester of the 16a,17o-ketal or acetal derivatives of 5u-bromopregnane-3B,6fl,16a,l7a-tetrol-20-one are then oxidized as by treatment with lead tetraacetate or with iodine and lead tetraacetate to yield the 3-ester of the l6a,17a-acetal or ketal derivatives of Sa-bromo-65,19- oxidopregnane-Bfl,l6a,l7u-triol-20-one (Compounds D).

These compounds are then hydrolyzed by treatment with a base such as carbonate to obtain the 16a,17u-ketal or acetal derivatives of 5'a-bromo-6B,l9-oxidopregnane 3fi,l6a,17a-triol-20-one (Compound D, wherein R is H).

The 160:,17oc-k6't31 and acetal derivatives of Soc-bIOmO- 6B, l9-oxidopregnane-3 8,16%17 Ot-tI'iOl-ZO-OHC (Compounds D) are then oxidized and dehydrobrominated in one step as by treatment with chromic anhydride and sulfuric acid to yield the 1601;17u-k6i3211 and acetal derivatives of 6,8,19- oxidoprogesterone (Compounds E).

Alternately the l6a,17a-ketal and acetal derivatives of Sa-bromo-6fi,19 oxidopregnane 3fi,16oc,17octriO1-20-Ono can be oxidized to the 16u,l7a-keta1 and acetal derivatives of Sa-brOmO-GB,l9-oxidopregnane-l6ot,17a-diol-3,20- dione (Compound F). Dehydrobromination of these latter compounds with a base such as potassium acetate in an appropriate solvent such as ethanol yield the 16oc,17o-k6tal and acetal derivatives of 6B,19-oxidoprogesterone.

When x and y are both saturated or are both unsaturated, the following alternate route from Compound V above is followed, R being selected from the group consisting hydroXy, acyloxy and OX0 (0 and P and Q are as hereinbefore defined:

In the first step, the starting materials are reduced as by treatment with zinc dust to yield the 3-acyloxy-6,l9- oxidopregnanes (Compounds G).

These intermediates (Compounds G, wherein R is acyl) are then treated with potassium carbonate in methanol to yield the 3-oxygen-ated-6,19-oxido derivatives (Compounds G, wherein R is oxo).

Compounds G may then be dehydrogenated as by treatment with 2,3-dichloro-5,6-dicyanoquinone, to yield the n fl-pregnadiene derivatives (Compounds H).

The preferred acyl groups in the compounds of this invention may be derived from hydrocarbon carboxylic acids of less than twelve carbon atoms as exemplified by the lower alkanoic acids (e.g., acetic, propionic, butyric and tert.-pentanoic), the monocyclic aryl carbocyclic acids (e.g., benzoic and toluic acids), aryl lower alkanoic acids (e.g., phenacetic and B-phenylpropionic acid), the cycloalkane carboxylic acids and the cycloalkene carboxylic acids and other like acids.

The compounds of this invention are physiologically active substances which possess progestational activity when administered both in the form of tablets or as a solution or suspension and hence can be used in lieu of known progestational agents such as progesterone in the treatment of habitual abortion for which purpose they can be administered in the same manner as progesterone, for example, the dosage being adjusted for the relative potency of the particular steroid.

The following examples are illustrative of the invention (all temperatures being in centigrade) Example 1.16a,1 7a- (fi-methyl-a-phenylmethylenedioxy -A -pregnene-3B-0Z-ZO-one 3-acetate To a solution of 0.5 ml. of 70% perchloric acid in ml. of freshly distilled acetophenone 10 g. of A -pregnene- 3B,16oc,17oc-tI10l-20-0I1e are added and the mixture stirred at room temperature for two hours. The solution is filtered from the small amount of insoluble material, then neutralized with dilute sodium bicarbonate diluted with water and extracted with chloroform. The chloroform is washed with water, dried over sodium sulfate and evaporated to dryness, in vacuo. The residue is dissolved in 30 ml. of pyridine and ml. of acetic anhydride and left at room temperature overnight. The ace-tic anhydride is decomposed with ice and the mixture distributed between chloroform and water. The chloroform is washed successively with 2 N HCl, 5% NaHCO and water and then evaporated to dryness in vacuo. Crystallization of the residue from acetone-hexane gives 7.0 :g. of 160:,17a- (5 methyl a phenylmethylenedioxy) A pregnene- 35-ol-20-one 3-acetate having a melting point of about 179-181, [M 47 (chloroform).

Example 2.5u-br0m0-1 6a,] 7 a-dimezhylmethy lene dioxypregnane-S 5, 6 5-di0l-2 O-one 3-acerate To a solution of 700 mg. of 16a,17a-dimethylmethylenedioxy-A -pregnene-35-ol-20-one 3-acetate in 16.5 ml. of dioxane containing 2.4 ml. of 0.5 M perchloric acid 440 mg. of N-bromoacetamide are added and the resulting solution kept in the dark at room temperature for two hours during which time it turns amber in color. A 5% solution of sodium sulfite is then added until the solution turns colorless. It is then diluted with 20 ml. of water and extracted with chloroform. The e'hloroform extracts are washed with water, then evaporated to dryness in vacuo. Crystallization of the residue from acetone-hexane gives 500 mg. of 5ocbrOm0-16 x,17a-dimethylmethylenedioxypregnane 35,65 diol 20 one 3-acetate having a melting point of about 158-160", [ac] 3.4 (chloroform).

Analysis.Calcd for C H O Br (527.49): C, 59.20; H, 7.45; Br, 15.15. Found: C, 59.93; H, 7.32; Br, 15.46.

Example 3.-5a-br0m0-1 6a,] 7 06- 5-methyl-a-phenylmelhylenedioxy pregnane-3 5,6 5-di0l-20-0ne 3 acetate Following the procedure described in Example 2 but substituting 16,170: (5 methyl oz phenylmethylenedioxy)-A -pregnene-35-ol-20-one 3-acetate for 160:,17adimethylmet'nylenedioxy A pregnene 35 ol 20- one 3-acetate, there is obtained 5oc-br0mO-16oc,17oc-(,B- methyl a phenylmethylenedioxy) pregnane 35,65- diol-ZO-one S-acetate having a melting point of about 184186, 34 (chloroform).

Analysis.-Calcd for C H O Br (589.56): C, 63.15; H, 7.01; Br, 13.55. Found: C, 63.21; H, 7.08; Br, 13.83.

Example 4 .5 ab1'0m0-65,I 9-0xid0-1 6 11,1 7 a-dim ethylm ethy lenedioxypregnane-35-0l-20-o/ze 3 -ace late A mixture of 870 mg. of lead tetraacetate which has been dried under high vacuum over potassium hydroxide for several hours and 260 mg. of calcium carbonate which has been dried over phosphorous pentoxide in 75 ml. of cyclohexane is refluxed for 15 minutes. Eight hundred and fifty-seven milligrams of 5a-bromo-16a,17a-dimethylmethylenedioxypregnane 35,65 diol one 3- acetate is then added and the mixture refluxed for 16 hours. The mixture is then filtered and washed successively with 50 ml. portions of methylene chloride and ethyl acetate. The combined filtrates are then washed with 100 ml. of 5% potassium iodide followed by 100 ml. of 10% sodium sulfite. The organic phase is then washed twice with water, dried over sodium sulfate and evaporated to dryness in vacuo. Crystallization of the residue from methanol gives 225 mg. of 5a-bromo-65,19- oxido 16a,17a dimethylrnethylenedioxy pregnane 35- ol-20-one 3-acetate having a melting point of about 203- 205 [a];;, -]-2 6.2 (chloroform).

Analysis.Calcd for C H O Br (525.48): C, 59.42; H, 7.10. Found: C, 59.51;H, 7.15.

6 Example 5 .5 a-br0m0-6 5,1 9-0xid0-1 6 a,] 7 a- 5-methyl-aph enylmethy lenedioxy pregnane-35-ol-20one 3-acetate Following the procedure described in Example 4 but substituting 5a bromo 16a,17a (5 methyl a phenylmethylenedioxy) pregnane 35,65 diol 20 one 3- acetate for the Sol-bromo-16a,17u-dimethylmethylenedioxypregnane-35,65-diol-20-one 3-acetate, there is obtained 5a bromo 65,19 oxido 16a,17 x (5 methyl uphenylmethy-lenedioxy) pregnaue 35 ol 20 one 3- 'acetate having a melting point of about 225-227, [M +5.0 (chloroform).

Analysis.-Calcd for C H O Br (587.55): C, 63.37; H, 6.69; Br, 13.60. Found: C, 63.41; H, 6.59; Br, 13.79.

Example 6 .5 abrom 0-6 5,1 9-0xid0-1 6 oc,] 7a-rlimetl2yl mezhy lenedioxypregnane-35-0l-20-0ne To a solution of 1 ml. of 10% potassium carbonate in 7 ml. of methanol mg. of 5a-bromo-65,l9-oxido- 16u,17a dimethylmethylenedioxypregnane 35 ol 20- one 3-acetate are added and the mixture stirred at room temperature for 16 hours. The solution is neutralized with 10% acetic acid and slowly diluted with water whereupon the 5u-bromo-65,19-oxido-16a,17a-dimethylmethylenedioxypregnane-35-ol-20-one crystallizes. It is filtered, washed with water and dried to give 58 mg. having a melting point of about 248250, [M +19.3 (chloroform).

Analysis.Calcd for C H O Br (483.44): C, 59.62. H, 7.30. Found: C, 59.44; H, 7.48.

Example 7 .5 a-brom 0-6 5,1 9-0xid0-1 6u-1 70t- (5-methy phenw lmethylenedioxy pregnane-35-0l-20-one Following the procedure described in Example 6 but substituting 50c bromo 65,19 oxido 16u,17a (5- methyl 0c phenylmethylenedioxy) pregnane 35 ol- 20-one 3-acetate for 50 bromo 65,19 oxido 1604,1700- dimethylmethylenedioxypregnane 35 o1 20 One 3- acetate, there is obtained 5a-bI'On10-6B,19-OXldO-16ec,l7oz- (5 methyl a phenylmethylenedioxy) pregnane 35- ol-20-one having a melting point of about 157.

Example 8.5a-br0m0-65,19-0xid0-16,17tx-dimethylmethyl enedioxy pregnane-3,20-dione To a stirred solution of 26.3 mg. of 5a-bromo-65,19- oxido 16a,17a dimethylmethylenedioxypregnane35-01- 20-one in 2 ml. of reagent grade acetone is added dropwise 0.21 ml. of a solution containing 200 mg. of chromic anhydride and 320 mg. of sulfuric acid in 9 ml. of reagent grade acetone and 1 ml. of WaterQAfter 5 minutes, the excess oxidizing agent is decomposed with a few drops of methanol and filtered. The filtrate is carefully diluted with water to give a crystalline precipitate of Set-bromo- 65,19 oxido 16a,17tx-dimethylmethylenedioxypregnane- 3,20-dione which is filtered, washed with water and dried. Melting point about 117130 (decomposition).

Example 9.5 a-brom 0-6 5,1 9-0xid0-J 6 0a,] 7oc- (5-methyl-aph enylmethylenedioxy -pregnane-3,20-di0ne Example 10.-65,19-0xido-16a,]7a-dimethylmethylenedi oxy progesterone To a solution of 169 mg. of 5a-bromo-65,19-oxido- 16a,17u dimethylmethylenedioxypregnane 35-o1-20-one in 10 ml. of reagent grade acetone, 1.55 ml. of a solution containing 200 mg. of chromic anhydride and 320 mg. of sulfuric acid in a mixture of 9 ml. of reagent grade acetone and 1 ml. of water are added dropwise. After 20 minutes the excess oxidizing agent is decomposed with methanol, the mixture centrifuged and the organic phase distributed between chloroform and water. The chloroform is separated and evaporated to dryness in vacuo with heat. Crystallization of the residue from acetone-hexane gives 6 ,8, l9-oxido- 1 6a, 17a-dimethylmethylenedioxyprogesterone having a melting point of about 213214, [M 46.1 (chloroform);

Mia. 237 i =13,800) y -Ca1cd for C H O (400.50): c, 71.97; H, 8.05. Found: C, 71.72; H, 8.32.

Example 1 1.-6[3,19-0 xid0-1 6a,] 7a-( fi-methyl-a-phenylmethylenediaxy)-progesterne Following the procedure described in Example 8 but substituting a bIOmO-6B,19-0X1d0-l60t,l7oc-(B-1I1fithYl-aphenylmethylene dioxy) pregnane-3fl-o1-20-one for 5abrorno 65,19 oxido 16a,17a-dimethylmethylenedioxypregnane 35 o1 20-one, there is obtained 6;3,19-oxidol6u,17a-(/3-methyl a phenylmethylenedioxy) progesterone having a melting point about 140142, [111 57 (chloroform),

ME 241 m (12,800)

Analysis.Calcd for C H O (462.53): C, 75.30; H, 7.41. Found: C, 75.24; H, 7.52.

Example 12.pNitr0acetophen0ne derivative of 613,19- oxido-l 6 0(.,1 7 a-dihydroxy-progestero ne (A) Following the procedure of Example 1 but substituting p-nitroacetophenone for acetophenone yields the 16a,l7u-nitroacetophenone derivative of A -pregnene-3flo1-20-one 3-acetate.

(B) Following the procedure set forth in Examples 2, 4,6 and 10 but employing the nitroacetophenone derivative obtained in Example 12 part (A), yields the nitr0ace tophenone derivative of 6B,19-oxido-16a,17a-dihydroxyprogesterone.

Example I3.Benzaldehyde derivative of 6f3,19-oxido 1 6 ,1 7oc-d ihydroxy progesterone Following the procedure set forth in Example 12, parts (A) and (B) but substituting 15 ml. of benzaldehyde for the p-nitroacetophenone of Example 12, part (A), yields the benzaldehyde derivative of 6B,19-oxido-16a,17a-dihydroxyprogesterone.

Example 1 4. -1 urfaral derivative of 6B,19-oxid0-16a,1 7ozdihy'droxy progesterone Following the procedure set forth in Example 12, parts (A) and (B), but substituting furfural for the p-nitroacetophenone of Example 12, part (A), yields the furfural derivative of 6,8,19-oxido-16a,17a-dihydroxyprogesterone.

Example 15.-p-Ch-l0r0acetophenone derivative of 6,8,19-

oxido-l 6a,1 7a-dihy droxyprogresterone Following the procedure of Example 12 parts (A) and (B), but substituting p-chloroacetophenone for p-nitroacetophenone of Example 12, part (A), yields the p-chloroacetophenone derivative of 16a,17a-dihydroxyprogesterone.

Example 16.5u-br0m0-6{3,1 9-0xi'd0-16a,1 7a-dim'ethylmethylenedioxypregnane-3fl-oZ-ZO-one 3-acetate with 50 ml. portions of methylene chloride and ethyl acetate. The combined filtrates are washed with ml. of 5% potassium iodide followed by 100 ml. of 10% sodium sulfite. The organic phase is then washed twice with water, dried over sodium sulfate and evaporated to dryness in vacuo. Crystallization of the residue from methanol gives 1.5 g. of 5a-bromo-6/3,19-oxido-16ot,17a-dimethylmethylenedioxypregnane-3[3-0l-20-one 3-acetate.

Example I 7.5a-br0m0-6{3,19-0xid0-16a,1 7a-(fi-methyla-phenylmethylenedioxy)-pregnane 3,8 0-l-20-0ne 3- acetate Following the procedure of Example 16 but substituting 5 a bromo-l6a,17a-(fi-methyl-a-phenylmethylenedioxy)- pregnane-BB,6fl-diol-20-one 3-acetate for the 5 a-bromo- 1604,1704 dimethylmethylenedioxypregnane-35,6;3-diol-20- one 3-acetate, there is obtained 5a-bromo-6fi,l9-oxido- 16,17/3 (B methyl-a-phenylmethylenedioxy)-pregnane- 3,8-01-20-one 3-acetate.

Example 18.6;3,19-0xid0-16a,]7a-dimethylmethylene dioxyprogesterone A solution of 50 mg. of 5a-brOIl'10-6B,l9-OXidO-16I3,l7mdimethylmethylenedioxypregnane-3,20-dione and 50 mg. of potassium acetate in 5 ml. of absolute ethanol are warmed at 60 C. for 2 hours. The solution is then cooled, diluted with water and extracted with chloroform. The chloroform phase is separated, washed with water and evaporated to dryness in vacuo. Crystallization of the residue from acetone-hexane gives 6,8,l9-OXidO-l6a,l7oc-dimethylmethylenedioxyprogesterone.

Following the procedure of Example 11 but substituting 50; brorno-6B,19-oxido-l6a,l7u-(fi-methyl-a-phenylmethylenedioxy) pregnane 3,20 dione for 5a bromo- 6 8,19 oxido 16a,17adimethylmethylenedioxypregnane- 3,20-dione, there is obtained 6,8,19 oxido -16a,17a-(,B- methyl-a-phenylmethylenedioxy -progesterone.

Example 20.Benz0phen0ne derivative of 613,19- oxido-I 6a,] 7a-dihy droxy progesterone Following the procedure set forth in Example 12, parts (A) and (B), but substituting benzophenone for the p-nitroacetophenone of Example 12, part (A) yields benzophenone derivative of 6,8,l9-oxido-l6a,l7a-dihydroxy progesterone.

Example 21.2-acetylfuran derivative of 6fl,19-

Oxide-16nd 7a-dihydr0xy progesterone Following the procedure set forth in Example 12, parts (A) and (B), but substituting 2-acetylfuran for p-nitroacetophenone of Example 12, part (A), yields Z-acetylfuran derivative of 6B,19-oxido-16 x,17u-dihydroxyprogres terone.

Example 22.Cycl0h'exylene derivative 0] 65,19- oxido-e,] 7a-dihydroxyprogesterone Following the procedure set forth in Example 12, parts (A) and (B) but substituting cyclohexanone for the pnitroacetophenone of Example 12, part (A), yields cyclohexylene derivative of 6,8,l9-oxido-l6a,17u dihydroxyprogesterone.

Example 23.-6(3,19-0xid0-16a,1 7a-dimethylmethylenedioxypregnane-SB-ol-ZO-one 3-Acetaze- To a solution of 5.45 g. of 50c-bIOII10-6/3,19-OXld0- 16a,17a-dimethylmethylenedioxypregnane-3[8 ol 20-one 3-acetate in 425 ml. of isopropanol is added 10 g. zinc dust and the mixture stirred under reflux for 24 hours. The mixture is cooled, filtered through celite and the precipitate washed with chloroform. The filtrate is diluted with 500 ml. of chloroform, washed with water and the organic phase is evaporated to dryness, in vacuo. Crystallization of the residue from the acetone-hexane gives 3.04 g. of

16a,170z dimethylmethylenedioxy A -pregnene 3,8,19- diol-ZO-one B-acetate, having a melting point of about 158160 C., [a] +3.6 (chloroform).

Anaylsis.--Calcd for C H O (446.56): C, 69.93; H, 8.58. Found: C, 70.14; H, 8.39.

The mother liquor from the crystallization is evaporated to dryness in vacuo, then redissolved in chloroform, and chromatographed on a plate using alumina (Activity V) as adsorbent with chloroform as the developing solvent. The band at Rf about 0.9 on elution with ethyl acetate, evaporation of the solvent in vacuo, and crystallization of the residue gives 6B,19-oxido-16a,17a-dimethylmethylenedioxpregnane-3j3-ol-20-one 3-acetate having a melting point about l68-170 C.

Analysis.Calcd for C H O (446.56): C, 69.93; H, 8.58. Found: C, 68.84; H, 8.60.

Example 24 .6 5,1 9-oxido-1 6 01,1 7a-( 8-methyl-a-phenylmethylenedioxy pregnane-3/3-0l-20-0ne 3 acetate Following the procedure of Example 23 but substituting 5a bromo 65,19 oxido 16a,17a-(fl-methyl-a-phenylmethylenedioxy)pregnane-3B-ol-20-one 3-acetate for 5abromo-6fi,l9-oxido 16a,17a dimethylmethylenedioxypregnane-3/8-ol-20-one B-acetate, there are obtained 65,19- oxido-16a,l7a-(B-methyl-a-phenylmethylenedioxy)- pregnane-3fl-ol-20-one 3-acetate having a melting point of l72173 C. 5.0 (chloroform).

Analysis.Calcd for C H O (464.59); C, 74.65; H, 8.21. Found: C, 74.70; H, 8.27.

Example 25.-6,B,19-xid0-16 x,1 7u-dimethylmethy lenedioxypregnane3/3-0l-20-0ne A mixture of g. of 613,l9-oxido-16a,17a-dimethylmethylenedioxypregnane-318-01 20-one 3-acetate in 300 ml. of methanol and 30 ml. of 10% potassium carbonate is stirred at room temperature for 16 hours. The solution is neutralized with acetic acid, diluted with water, and extracted with chloroform. The chloroform extracts are washed with water and evaporated to dryness in vacuo. Crystallization of the residue from acetone-hexane gives 2.75 g. of 6,8,19-oxido-l6a,17u-dimethylmethylenedioxypregnane-3fi-ol-20-one having a melting point of 25 9261 C. +495 (chloroform).

Analysis.Calcd for C H O (466.59): C, 74.65 H, 8.21. Found: C, 74.70; H, 8.27.

Following the procedure of Example 25 but substituting 6,8,19-oxido-l6u,17a-(fi methyl a phenylmethylenedioxy)-pregnane 3fi-ol-20-one 3-acetate for the 613,19- OXldO-16oc,17a dimethylrnethylenedioxypregnane 3,8-01- 20-one 3-acetate, there is obtained 6/3,19-OXldO-16oc,-17a- (fl-methyl-a-phenylmethylenedioxy)pregnane 35-01-20- one having a melting point of 172173 C., [0:]; 5.0 (chloroform).

AnaIysis.-Calcd for C H O (466.59). C, 74.65; H, 8.21. Found: C, 74.70; H, 8.27.

Example 27.6/8,19-0xid0-16a,17a-dimethylmethylenedioxypregnane-3,20-dione To a solution of 61.5 mg. of 6,8,19-0Xid0-16a,17a dimethylmethylenedioxypregnane-3;3-ol-20-one in 5 ml. of purified dioxane there is added dropwise an aqueous solution containing 200 mg. of chromic anhydride and 320 mg. of sulfuric acid per ml. until the oxidizing reagent is no longer decolorized. After 5 minutes, the excess oxidizing agent is decomposed with methanol, the mixture diluted with water and extracted with chloroform. The chloroform is washed with water and evaporated to dryness in vacuo. Crystallization of the residue from acetonehexane gives 66 mg. of 6p,19-oxido-16a,17a-dimethylmethylenedioxypregnane-3,ZO-dione having a melting point of l74175 C., +82.4 (chloroform).

Analysis.CalCd for C24H3405; C, H, 8.51, Found: C, 71.79; H, 8.40.

to Example 28.6fl,1 9-0xid0-1 6 11,1 7 afi-methyl-uphenylm'ethylenedioxy pregnane-3,20-di0ne Following the procedure of Example 27 but substituting 618,19-oxido-16a,17a,-(fi-methy1 a phenylmethylenedioxy)-pregnane-3,B 01-20 one for the 619,19 oxido- 16a,17a-dimethylmethylenedioxy-pregnane-35-01-20 one, there is obtained 6/8,19-oxido-16a,17u-(fl-methyl-a-phenylmethylenedioxy)pregnane-3,20-dione.

Example 29.6,8,]9-0xid0-16a,17u-dimethylmethylenedioxy-Z dehydroprogesterone max. 244 mp (e=12,000) Example 30.6;6,19-oxid0-16a,17a-dimethylmethylenedioxy-1 dehydroprogesterone Following the procedure of Example 29', but substituting an equivalent amount of 6B,19-0Xld0-16oz,17nL-CliII1Bthyhnethylenedioxyprogesterone for 6fl,l9-OXiClO-16oc,l7ocdimethyhnethylenedioxypregnane-3,ZO-dione, there is obtained 6,3, 19-0Xid0-160c, 17a-dimethylmethylenedioxy-ldehydroprogesterone.

Example 3] .6B,] 9-0xido-16u,.] 7 ocfl-methy l-a-pheny lmethylenedioxy 1-dehydr0pr0gester0ne Following the procedure of Example 29 but substituting 6,8,19 oxido :,17oc (B methyl 0L phenylmethylenedioxy) -pregnane-3,20-dione for 6B,19-OXld O-160L,17ocdimethylmethylenedioxypregnane-3,20-dione or 613,19- oxido 16a,17x 8 methyl a phenylmethyleneprogesterone for 6p,l9-oxido-l6a,17a-dimethyl1nethylenedioxyprogesterone in Example 30, there is obtained 65,19- oxido l6a,17u (B methyl oz phenylmethylenedioxy 1 dehydroprogesterone.

What is claimed is:

1. A steoroid of the formula wherein the x and y linkage is saturated or double bonded; P is selected from the group consisting of hydrogen, lower alkyl, halo lower alkyl, carboxy lower alkyl, lower alkanoyloxy lower alkyl, monocyclic cycloalkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic and monocyclic heterocyclic lower alkyl, Q is selected from the group consisting of lower alkyl, halo lower alkyl, carboxy lower alkyl, monocyclic cycloalkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic and monocyclic heterocyclic lower alkyl; and together with the carbon atom to which they are joined, P and Q are selected from the group consisting of cycloalkyl and monocyclic heterocyclic.

2. A compound of the formula wherein P and Q have the same meaning as in claim 1.

3. A compound of the formula 6. 613,19 oxido 16a,17a dimethylmethylenedio-xy 7. 65,19 oxido 16a,17oc ([3 methyl a pheny1-- methylenedioxy pregnane-3 fi-o1-20-0ner 8 66,19 oxido 16u,17a dimethylmethylenedioxypregnane-LZO-dione.

9. 613,19 oxido 16a,17u (,8 methyl a phenylmethylenedioxy) pregnane-3,20-dione.

10. 613,19 oxido 16a,17a dimethylmethylenedioxyl-dehydroprogesterone. 7

No references cited.

LEWIS GOTTS, Primary Examiner.

H. FRENCH, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,326,904 June 20, 1967 Patrick A. Diassi It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 2, line 45, for "cyclohexanone" read cyclodexanone column 6, line 42, for "16,1701" read 16a,l7a column 7, line 17, after "phenylmethylene" strike out the hyphen; column 8 line 22 for "168,17a" read 16a ,17a

column 9, line 27, for "C read C lines 43 and 44,

for "C29H38O5 (466.59): c, 74.65; H, 8.21. Found: c, 74.70; H, 8.27." read 0 11 0 (404.55): c, 71.24; H, 8.97. Found:

C, 71.29; H, 8.98. column 10, line 24, for "12,000" read 12,800

Signed and sealed this 2nd day of July 1968.

(SEAL) Attest:

EDWARD J. BRENNER Commissioner of Patents Edward M. Fletcher, J r.

Attesting Officer v 

1. A STEOROID OF THE FORMULA 